The treatment of pathological conditions requiring a continuous supply to the body of substances of therapeutic interest has made necessary the development of devices which can be implanted in a patient and which are capable of releasing these substances efficiently and sometimes for long periods of time.
To satisfy this need, bioartificial organs have been developed which contain cells producing one or more substances of therapeutic interest. The cells contained in a bioartificial organ are confined in internal spaces, or encapsulation chambers, delimited by at least one semi-permeable membrane. Such a semi-permeable membrane should allow the diffusion of substances of therapeutic interest to the target cells in the patient's body, while being impermeable to the antibodies and cells of the patient's immune system.
The expression artificial organ is understood to mean a device comprising at least one encapsulation chamber consisting of at least one semi-permeable membrane; said encapsulation chamber is intended to contain cells secreting a substance of therapeutic interest.
The substance of therapeutic interest may be a neurotransmitter, a hormone, a growth factor or a cytokine; for example and with no limitation, insulin, growth hormone, calcitonin.
One example of this type of device is described in international application WO 02/060409 which is aimed more particularly at the development of semi-permeable membranes with improved mechanical and selective permeability properties for the production of bioartificial organs consisting of a chamber for encapsulating cells producing an active substance. Implanted in the patient, such a bioartificial organ allows the release of the active substance and the treatment of the patient.
A difficulty encountered during the implantation of this type of device is the relatively short duration of its efficacy which can be explained by a lack of oxygenation of the cells encapsulated in the encapsulation chamber and their inactivation by low molecular weight cytokines produced by the immune cells of the recipient patient.
Sigrist et al. improved the viability of pancreatic islets encapsulated in an encapsulation chamber consisting of a semi-permeable membrane made of sodium polyacrylonitrilemethallylsulfonate (“AN69” membrane from the company HOSPAL) by adding, inside this chamber, the epithelial cell growth factor (VEGF). After implanting in mice a bioartificial organ consisting of the encapsulation chamber thus prepared, the division of VEGF into the tissues surrounding the implant allowed the induction of angiogenesis around the implant (J. of Vascular Research, 2003, 40(4):359-67 and Cell Transplantation, 2003, vol. 12, pp. 627-635).
This technique has however limits linked to the low diffusibility of the VEGF across the walls of the chamber and to the importance of inducing angiogenesis as early as possible after the implantation of the bioartificial organ.
U.S. Pat. No. 5,262,055 provides an artificial pancreas consisting of an encapsulation chamber equipped with an immunoprotective membrane and which contains pancreatic islets in a heat-sensitive polymer matrix; the contents of the encapsulation chamber may be replaced after implantation by means of two fine tubes which connect the inside of the encapsulation chamber to the outside of the patient's body. The immunoprotective nature of the semi-permeable membrane is conferred by the impermeability of the membrane which prevents the entry into the device of cells of the immune system. This patent also proposes the incorporation, into the heat-sensitive polymer matrix, of polymer microparticles allowing the release of active agents intended to induce vascularization or to inhibit macrophage activity around the encapsulation chamber. The double disadvantage of this device is the location of the polymer microparticles inside the encapsulation chamber (low diffusibility of the semi-permeable membrane) and the release and then the undesirable accumulation in the body of the polymer constituting the microparticles during the release of the active agents.
International application WO 94/26399 describes semi-permeable membranes which bear active agents attached by covalent bonds; this type of membrane is however not satisfactory because their preparation requires an additional step of covalent attachment of the active agents and in that the quantity of active agents is limited to that present at the surface of the membrane.
Application US 2006/0198864 describes membranes for biological interfaces intended to cover implanted devices such as probes for measuring blood glucose. These membranes have an architecture in two parts, the supporting layer and the external layer which has a very marked relief (honeycomb architecture having cavities 20 to 1000 μm in size) and which allows the development of blood vessels. This document also describes the possibility of adding active agents to these membranes in particular in order to limit inflammatory manifestations and to promote vascularization; these agents are then either incorporated into the matrix of the membrane (composed of polycarbonate, PVA or cellulose polymers) or adsorbed or linked by covalent bonds at the surface of the membrane. The use of these membranes for the production of probes intended for the detection of substances such as glucose in the body requires a particular relief and high permeability of the membranes; the inventors observed that the particular structure of these membranes, in particular, the fact that their pores are interconnected (which leads to the obstruction of the pores by cells, thus preventing the circulation of the biologically active molecules and of substances of therapeutic interest), that the supporting layer does not have a cut-off that is specifically chosen to ensure selective permeability and that the hydrophobic materials are used for the production of the external layer of these membranes, means that these supports are not compatible with their use for the preparation of a bioartificial organ and for its operation after implantation in an individual.
Accordingly, several difficulties are encountered during the implantation of a bioartificial organ in a recipient patient; in the first place, it will be necessary to avoid or limit (i) the inflammatory reaction of the patient's tissues caused by the fitting of the bioartificial organ and (ii) the introduction into the reaction chamber of cytokines and chemokines which would destroy the secretory cells. In addition, oxygenation of the secretory cells encapsulated into the bioartificial organ and optimum diffusion of the substance of therapeutic interest into the body require vascularization of the tissues surrounding the bioartificial organ. It is still therefore necessary to improve the properties of the membranes used for the production of bioartificial organs in order to accelerate the implantation and the initiation of operation (secretion of substances of therapeutic interest) of said bioartificial organs in the body of patients.